PHARMACOKINETICS OF FK-506, A NOVEL IMMUNOSUPPRESSANT, AFTER INTRAVENOUS AND ORAL ADMINISTRATIONS TO RATS

A pharmacokinetic study of FK-506 (FK), a novel immunosuppressant being about hundred times more potent than cyclosporin A (CyA) in the in vitro experiment, has been performed in rats after intravenous and oral administrations at two doses, 1.0 and 5.0 mg/kg. As compared with CyA, plasma, bile, urine and lymph FK levels were determined by a fluorescence high-performance liquid chromatographic method with chemiluminescence detection. Non-compartment pharmacokinetic parameters were calculated by area/moment analysis. After the i.v. injection of FK at 1.0 and 5.0 mg/kg, the total plasma clearance, CL(tot), was 7.028 +/- 0.076 (mean +/- S.E.) and 7.651 +/- 0.755 ml/min, steady-state distribution volume, V(d,ss), was 4623 +/- 28 and 4201 +/- 529 ml/kg, elimination half-life at the terminal elimination phase, t1/2-beta, was 2.36 +/- 0.25 and 2.54 +/- 0.29 h, and the volume of the initial distribution space, V1, was 1336 +/- 150 and 1065 +/- 115 ml/kg, respectively. By comparing the pharmacokinetic parameter with CyA, the CL(tot) of FK is about three times greater than that of CyA. There is not a significant difference on t1/2-beta between CyA and FK. The V1 and V(d,ss) of FK are 4-5 times greater than that of CyA. Therefore, higher clearance of FK is ascribed not only to the faster elimination from the rat body but also to the greater distribution space in the body. The mean percentage of FK transferred into the thoracic lymphatics over 6 h were 0.09 +/- 0.02% (1.0 mg/kg) and 0.16 +/- 0.02% (5.0 mg/kg), respectively. As the mean percentages of FK excreted into both the bile and urine for 6 h after i.v. injection were 0.0744 +/- 0.0177% and 0.0073 +/- 0.0018%, respectively, the main elimination pathway of this drug is thought to be the metabolism in the body. To the other groups of rats, FK was administered intraduodenally, 5.0 mg/kg, in two kinds of liquid preparations, and both the systemic and lymphatic availabilities were studied. The mean systemic availabilities of FK were 11.3% and 23.5% from the two preparations. The lymphatic availability of this drug over the experimental period, 6 h, was less than 0.2%. These results suggest that FK distributes more extensively in the rat body than CyA.